Phage and Antibiotic Combination Therapy for Use on Polymicrobial Infections

用于多种微生物感染的噬菌体和抗生素联合疗法

• 批准号: 10304840
• 负责人: Catherine Maylin Loc Carrillo
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304840
• 关键词: Abscess; Address; Anti-Bacterial Agents; Antibiotics; Appearance; Bacteria; Bacterial Antibiotic Resistance; Bacterial Counts; Bacterial Infections; Bacteriophages; Biological Availability; Bioluminescence; Bioreactors; Cefepime; Centers for Disease Control and Prevention (U.S.); Clinical; Combined Antibiotics; Combined Modality Therapy; Communicable Diseases; Communities; Cutaneous; Department of Defense; Development; Disease Management; Dose; Formulation; Genus staphylococcus; Goals; Government Agencies; Gulf War; Health care facility; Hospitals; Hour; Hydrogels; In Vitro; Individual; Infection; Injury; Intervention; Intravenous; Length of Stay; Liquid substance; Long-Term Care; Medical; Membrane; Microbial Biofilms; Modeling; Monitor; Organism; Outcome; Patients; Placebos; Preparation; Protocols documentation; Pseudomonas; Pseudomonas aeruginosa; Public Health; Quality of Care; Rattus; Renal function; Reporting; Reproducibility; Research; Resort; Saline; Site; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus; Techniques; Testing; Time; Treatment Cost; Update; Vancomycin; Veterans; Wound Infection; Wound models; active duty; acute care; alternative treatment; antimicrobial; combat injury; combat wound; cost; drug release kinetics; efficacy testing; in vivo imaging system; methicillin resistant Staphylococcus aureus; mortality; multi-drug resistant pathogen; multidrug-resistant Pseudomonas aeruginosa; non-invasive monitor; novel; pathogen; polymicrobial biofilm; pre-clinical research; prevent; safety and feasibility; side effect; subcutaneous; systemic toxicity; time use; wound; wound treatment

Despite current infection intervention strategies implemented to treat combat-related injuries, one-third of such injuries are complicated by infections. Infections acquired during active duty or while being treated at Department of Defense facilities or various healthcare facilities have been found to persist after patients enter a VA facility. There has been an increase in the complexity of infectious disease management reported on Veterans who suffered from combat wounds obtained during the Gulf War era. The rise in antibiotic-resistant bacterial infections presents a threat to public health and the economy. Approximately one-third of Veterans admitted to VA acute care medical facilities have both multi-drug resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Patients colonized with these pathogens can bring the organism into hospitals and long-term facilities where it can spread and infect susceptible patients. Patients suffering from infections by these multi-drug resistant organisms (MDRO's) result in higher treatment costs, longer hospital stays, and higher rates of mortality compared to patients with susceptible bacterial infections. There is a need to investigate alternative or complimentary treatments to the currently available therapies such as the use of last-resort antibiotics. We hypothesize that a combination of a phage cocktail AND anti- Staphylococci and antipseudomonal antibiotics delivered in a hydrogel can be developed to prevent and treat polymicrobial wound infections. We propose to do this by: 1) Determine the optimal formulation of phage- antibiotic combination (PAC) treatment in vitro. Cefepime, vancomycin and a phage cocktail (i.e., phages against Staphylococci and Pseudomonas) will be formulated and tested against clinical strains to determine optimal concentrations of the antibacterial agents needed to kill the target bacteria. The release rate of the drugs and phages from a hydrogel will be determined. We will then: 2) Develop a polymicrobial wound infection in a rat model by establishing a subcutaneous wound infection caused by both MRSA and P. aeruginosa over a 14-day period. Bioluminescent bacteria will be used to develop a polymicrobial wound infection (i.e. cutaneous abscess), which will be monitored in real-time using an in vivo imaging system. Lastly, we will: 3) Assess the efficacy of locally administered PAC at treating wound infection in a rat wound model. Our polymicrobial wound infection model will be used to the test the efficacy of the following treatments: a) single dose of locally administered PAC hydrogel; b) repeated doses of locally delivered PAC hydrogel; c) systemic administration of liquid PAC administered every 12 hours; d) placebo (i.e. saline in hydrogel) delivered locally administered every 12 hours. Parameters assessed will include level of bacterial bioluminescence, gross wound appearance and renal function over time. Bacterial counts in the wound at the completion of treatment will also be assessed. Our phage and antibiotic combination (PAC) hydrogel will provide the requisite local concentrations of antibacterial agents to kill MRSA and P. aeruginosa while minimizing systemic concentrations and the associated undesirable side effects. Our goal is to formulate the optimum concentration of phages and antibiotics in a hydrogel and assess the feasibility and efficacy to treat polymicrobial wound infections in a rat wound model. The development of our PAC treatment could have a profound impact on the medical community by presenting an alternative treatment to control difficult bacterial infections caused by multi-drug resistant organisms.

尽管目前实施了目前的感染干预策略来治疗与战斗有关的伤害，但其中三分之一此类 感染使伤害复杂。在现役期间或在接受治疗时获得的感染 国防部设施或各种医疗保健设施在患者进入后持续存在 VA设施。报道的传染病管理的复杂性有所提高 遭受海湾战争时代遭受战斗伤口的退伍军人。 抗生素耐药细菌感染的增加对公共卫生和经济构成了威胁。 接纳VA急诊医疗设施的退伍军人中约有三分之一具有多药的耐药性 铜绿假单胞菌和耐甲氧西林金黄色葡萄球菌（MRSA）。与患者定居 这些病原体可以将有机体带入医院和长期设施，在那里它可以传播和感染 易感患者。这些多药耐药生物（MDRO）感染的患者 与患者相比 易感细菌感染。 有必要调查当前可用疗法此类替代或免费治疗 作为最后一度抗生素的使用。我们假设噬菌体鸡尾酒和反 - 可以开发在水凝胶中递送的葡萄球菌和抗血素抗生素，以预防和治疗 多因素伤口感染。我们建议通过：1）确定噬菌体的最佳公式 体外抗生素组合（PAC）处理。头孢菌素，万古霉素和噬菌体鸡尾酒（即噬菌体 针对葡萄球菌和假单胞菌）将针对临床菌株制定和测试，以确定 杀死靶细菌所需的抗菌剂的最佳浓度。释放率 将确定水凝胶的药物和噬菌体。然后，我们将：2）形成多菌伤口 通过建立由MRSA和P。 在14天的时间内铜绿。生物发光细菌将用于发育多因素伤口 感染（即皮肤脓肿），将使用体内成像系统实时监测。最后， 我们将：3）评估在大鼠伤口模型中治疗伤口感染时局部施用的PAC的功效。 我们的多数伤口感染模型将用于测试以下疗法的功效：a） 单剂量的局部施用PAC水凝胶； b）重复剂量的局部递送的PAC水凝胶； c） 每12小时一次给药的液体PAC的系统性给药； d）安慰剂（即水凝胶中的盐水） 每12小时交付一次本地管理。评估的参数将包括细菌的水平 随着时间的推移，生物发光，总伤口外观和肾功能。伤口中的细菌计数 还将评估治疗的完成。 我们的噬菌体和抗生素组合（PAC）水凝胶将提供必要的局部浓度 杀死MRSA和铜绿假单胞菌的抗菌剂，同时最大程度地减少全身浓度和 相关的不良副作用。我们的目标是制定噬菌体的最佳浓度和 水凝胶中的抗生素并评估治疗大鼠多因素伤口感染的可行性和功效 伤口模型。我们PAC治疗的发展可能会对医学产生深远的影响 通过提出另一种治疗方法来控制由多药物引起的困难细菌感染 抗性生物。